Vaso-occlusive painful episodes (VOE) in sickle cell disease (SCD) are the leading cause of hospitalizations, emergency department (ED) visits & are associated with increased mortality. Treatment options are limited. Since we discovered that children with SCD & VOE have low arginine levels, we performed a randomize, double-blinded, placebo-controlled trial of arginine therapy in 54 children with VOE requiring hospitalization. We observed a 54% reduction in total opioid use & significantly lower pain scores at discharge in children who received 5 days of 100 mg/kg/dose TID IV arginine therapy compared to placebo, as well as a clinically relevant trend in reduced length of hospital stay of nearly 17 hours. Arginine is a safe & inexpensive intervention with narcotic-sparing effects in pediatric SCD patients with VOE. This application will develop the infrastructure to design a pivotal clinical tral using arginine as a novel treatment of VOE in children with SCD that may change clinical practice. Aim 1 will perform critical pharmacokinetics (pK) and pharmacodynamics studies currently lacking, to evaluate bolus dosing vs. continuous infusion of arginine therapy to identify the optimal dose to achieve and maintain plasma arginine levels sufficient for intracellular arginine transport & maximal nitric oxide (NO) production. Baseline & daily plasma arginine & its metabolites, arginase, intracellular erythrocyte arginine concentration, urinary arginine, arginine analogs, & NO metabolites will be measured together with 8-hour pK data obtained in 21 hospitalized patients. Clinical outcomes such as time-to-pain- crisis-resolution, length of ED & hospital stay, total opioid use, & pain scores will be obtained. Aim 2A will create a standardized ED-based pain therapy protocol based on national standards that will be shared with all potential sites, which include 17 high-volume Pediatric Emergency Care Applied Research Network (PECARN) & non-PECARN EDs. Site variability from this standard practice will be prospectively identified by chart review of 20 consecutive charts at each site. Aim 2B will collect feasibility data on volume & admission rates from the EDs of potential sites on all eligible patients with SCD & VOE evaluated over a 12-month period in order to demonstrate sufficient access to the targeted study population within the proposed network. Aim 3 will establish a network of clinical investigators highly experienced in the design & successful completion of clinical trials in SCD-VOE. We have assembled a highly experienced Protocol Steering Committee with expertise in SCD clinical trials, & obtained the endorsement of PECARN, the only federally-funded pediatric ED network in the U.S. PECARN participation will insure access to high-volume pediatric EDs with a strong research track record & success in ED-based multi-center trials. Completion of these aims will provide data necessary to identify optimal dosing strategy for arginine therapy, establish a clinical network, data coordinating plan, an ED- based pain protocol and a completed protocol for a phase III clinical trial of L-arginine for the treatmet of vaso- occlusive pain in children with SCD to be submitted for NIH funding.